TWI553000B - Trans-2-nonadecyl-4-hydroxymethyl-1,3-dioxolane and method for producing thereof - Google Patents

Description

Trans-2-19 alkyl-4-hydroxymethyl-1,3-dioxolane compound and preparation method thereof

The present invention relates to a compound and a process for the preparation thereof, and in particular to a trans-2-19 alkyl-4-hydroxymethyl-1,3-dioxolan compound and a process for the preparation thereof.

According to the liver disease system, it has become a major concern for the health of modern people. Furthermore, factors such as alcohol, drugs, drugs or viruses can cause persistent or repeated chronic liver parenchymal inflammation, resulting in sustained damage to liver cells, even necrosis, which exposes individuals to high risks of liver diseases such as fatty liver and cirrhosis. It is extremely likely to develop into liver cancer. The liver fibrosis is a pathological phenomenon caused by chronic liver damage. The main cause is that when the liver cells suffer sustained and long-term damage, the proliferation and decomposition of liver fibrous connective tissue is in an imbalance, and the extracellular matrix in the liver is excessive. Deposition, and liver fibrosis is also a necessary process for the conversion of chronic liver disease into cirrhosis or liver cancer.

Liver fibrosis is not an irreversible process. Currently, there are a few effective drugs available for the treatment of liver fibrosis, such as colchicine, paracortin, interferon, etc. However, these drugs still have side effects. And these drug cords can only block part of the liver fibrosis, and can not achieve the effect of comprehensive inhibition of fibrosis. In addition to western medicine, there are many herbal medicines in the Chinese medicine department that can be used to treat liver fibrosis, such as Tanjung, Sanqi, Armor, Bupleurum, etc. The use of Chinese herbal medicine can reduce the side effects on the individual. However, if the Chinese herbal medicine takes a long time to be effective, it will cost more, and in the case where the source of Chinese herbal medicine is unknown, it may still be contaminated with undesirable ingredients and affect its effectiveness.

In addition, some of the ingredients have the function of strengthening immunity, and have the effect of treating liver diseases. Generally, they are commonly used, such as cockroaches. However, it is necessary to take a large amount of daily dose to achieve the effect on the individual. There are also difficulties in its implementation. In order to avoid the above-mentioned defects, for example, in Taiwan Patent No. I370747, the meat is first extracted with alcohol, and then purified by a column to obtain an active substance against liver fibrosis, but it is disclosed in the prior art. The extraction and purification methods are required to obtain the active substances through complicated steps. In other words, the methods disclosed in the prior art include the following defects: First, a large amount of hydrazine is required as a raw material, resulting in a mass production cost that is too expensive; The secondary purification step can be used to obtain the active material, and the yield is too low.

Accordingly, the prior art still lacks an effective ingredient having specific curative effect on liver fibrosis and low side effects. Therefore, an important issue at present is to develop a substance which has low manufacturing cost, low side effects, and can effectively inhibit liver fibrosis. It can be used as a clinical treatment for liver related diseases.

The main object of the present invention is to provide a trans-2-nonadecyl-4-hydroxymethyl-1,3-dioxolane (trans-2-nonadecyl-4-hydroxymethyl-1,3-dioxolane). Or a pharmaceutically acceptable salt thereof, wherein the trans-2-19 alkyl-4-hydroxymethyl-1,3-dioxolan compound is as shown in the formula (I):

Another object of the present invention is to provide a method for producing a trans-2-19 alkyl-4-hydroxymethyl-1,3-dioxolane compound or a pharmaceutically acceptable salt thereof. (II) Compound: And the compound of formula (III): The acetal reaction is carried out to obtain a mixture containing the compound of the formula (I).

Wherein: in an embodiment of the invention, the compound of formula (II) is a compound of formula (IV): And formed by oxidation reaction with pyridinium chlorochromate in an organic solvent.

In an embodiment of the invention, an acid catalyst is present in the acetal reaction.

In an embodiment of the present invention, the mixture containing the compound of the formula (I) is purified by a separation technique including, but not limited to, column chromatography, levee separation or the technical field of the art. And the methods that are commonly known to those who are knowledgeable.

The first figure is a ¹ H-NMR spectrum of the active ingredient obtained in Example 2 of the present invention.

The second figure is a ¹³ C-NMR spectrum of the active ingredient obtained in Example 2 of the present invention.

The third panel is a mass spectrum of the active ingredient obtained in Example 2 of the present invention.

Hereinafter, a few examples will be given to further illustrate the present invention as follows.

Example 1: Preparation of a compound of formula (I)

First, we will equal It is dissolved in dichloromethane (CH ₂ Cl ₂ ) together with pyridinium chlorochromate (PCC), and stirred and mixed at 30 ° C, wherein, in the present example, the compound of formula (IV) and chromium chrome The acid pyridinium salt was 1 gram and the dichloromethane was 20 ml. The dichloromethane solution containing the compound of the formula (IV) and the pyridinium chlorochromate is subjected to suction filtration with celite to obtain a filtrate, and then the filtrate is concentrated under reduced pressure to obtain a compound of the formula (II): It is a white solid. The reaction formula of the above chemical reaction is as follows.

The compound of formula (II) is dissolved in 50 ml of toluene and 700 mg of the compound of formula (III) is added: And 300 mg of p-toluenesulfonic acid ( TSOH ) was heated to reflux for about 3 hours. The reaction-completed solution was subjected to removal of toluene under reduced pressure, and then added to a 20% aqueous solution of sodium carbonate (Na ₂ CO ₃ ) at a concentration of 1%, and extracted three times with ethyl acetate. The extract is collected and the ethyl acetate is removed by concentration under reduced pressure to give a mixture containing the compound of formula (I): . The reaction formula of the above chemical reaction is as follows.

In order to obtain a purified compound of the formula (I), the mixture is dissolved in 5 ml of hexane, and a white compound of the formula (I) is isolated by a gel column chromatography, a total of about 260 mg, wherein the rubber tube The extract used in the column chromatography was hexane/ethyl acetate (9:1).

Example 2: Self-purification of active ingredients with liver protection function

Referring to the content of the prior art, after taking 65 kilograms, after peeling, about 27.7 kilograms of meat is obtained. The meat is dried by hot air, and the dried meat is about 2.5 kg in weight, and then immersed in an alcohol of about 3 times the amount of dried oyster meat, and extracted to obtain about one kilogram of the wine cellar extract.

900 grams of the wine cellar extract was mixed with water and ethyl acetate in a ratio of 1:2:3 by volume, and then separated and extracted by a separating funnel to obtain an ethyl acetate layer, and the ethyl acetate layer was concentrated and frozen. Drying, an ethyl acetate cellar extract was obtained, and 900 g of ethyl acetate layer was taken and separated by column chromatography, and adsorbed by silica gel (40-63 pores), followed by a ratio of hexanol:ethyl acetate. 10:1, 5:1, 3:1, 1:1, 1:3, 1:5 and 1:10 and methanol extraction, 18 fragments were obtained. The 18 fragments were analyzed by thin layer chromatography ( TLC ) to isolate a liver-protecting active ingredient, about 1 gram, wherein the liver-protecting effect of the active ingredient was in Taiwan patent. I370747 is disclosed, so there is no rumor.

The active ingredient is a white solid, having a melting point of about 51 ° C, a specific optical rotation [α] D25 + 1.15 (c 0.75 methanol), and a thin layer chromatography with a hexane/ethyl acetate ratio of 4:1. The active ingredient has an Rf of exactly 0.3. Further, the active component is analyzed by a hydrogen nuclear magnetic resonance spectrometer ( ¹ H-NMR) and a carbon 13 nuclear magnetic resonance spectrometer ( ¹³ C-NMR), and the obtained spectrum is as shown in the first diagram and the second diagram, wherein The solvent used was deuterated chloroform (CDCl3), and the hydrogen nuclear magnetic resonance spectrometer was 400 MHz. From the first figure, the δ _H value of the active ingredient is 4.96 (1H, t, J = 4.8 Hz, H-2), 4.17 (1H, m, H-4), 4.08 (1H, dd, J = 8.4). , 6.4 Hz, H-5 _a ), 3.67 (1H, dd, J = 11.6, 3.6 Hz, H-6 _b ), 3.62 (1H, dd, J = 8.4, 7.2 Hz, H-5 _b ), 3.58 ( 1H, dd, J = 11.6, 5.6 Hz, H-6 _b ), 2.15 (1H, br. s, 6-OH), 1.59-1.63 (2H, m, H-1'), 1.27-1.43 (2H, m, H-2'), 1.01-1.25 (32H, br s, H-3'-18'), 0.87 (t, 3H, J = 6.6 Hz, H-19'); I) The δ _C value of the compound is 104.7 (C-2), 76.1 (C-5), 66.5 (C-4), 62.6 (C-6), 34.1 (C-1'), 31.9 (C-17' ), 29.3-29.9 (C-3'-16'), 24.0 (C-2'), 22.7 (C-18'), 14.1 (C-19').

Further , the active ingredient was analyzed by an Electro Impact-Mass Spectrophotometer ( EI-MS), and the results are shown in the third figure. From the third figure, the molecular ion peak [M] + mass-to-charge ratio (m/z) and relative intensity (%) of the compound of formula (I) are 370 (20), 355 (65), 341 (22), 327 (11). ), 267(5), 185(3), 157(9), 103(100), 57(51).

Comparing the obtained compound of the formula (I) of the first example with the active ingredient obtained in the second embodiment, the compound of the formula (I) prepared by the method of the present invention is consistent with the structure of the active ingredient obtained in the second embodiment, in other words, the present invention is disclosed. The compound of the formula (I) has the effect of preventing or treating liver diseases, especially liver diseases associated with liver fibrosis, and thus an effective amount of the compound of the formula (I) is used as an active ingredient of a pharmaceutical composition or is prepared as a daily nutrient. Supplements. Furthermore, by the method disclosed in Example 2, only 2 g of the active ingredient can be obtained with 27.7 kg of meat, and the yield is only 0.004%. In contrast, the method disclosed in the present invention obtains only 260 using only 2 g of the raw material. The compound of formula (I) in milligrams has a yield of 13%, which is significantly higher than the method disclosed in the prior art. Accordingly, the preparation method of the present invention can effectively achieve the effect of increasing the yield of the compound of the formula (I) and at the same time reducing the production cost.

The present invention has been described in detail by the embodiments of the present invention. It should be understood that those skilled in the art, without departing from the spirit of the invention, The range of yokes obtained.

Claims (4)

One will prepare a compound of formula (I): (I) A method of formulating a compound of formula (II): (II) and compound of formula (III): (III), an acetal reaction is carried out to obtain a mixture containing the compound of the formula (I). According to the method of claim 1, wherein the compound of the formula (II) is a compound of the formula (IV): (IV) is formed by an oxidation reaction with pyridinium chlorochromate in an organic solvent. According to the method of claim 1, wherein an acid catalyst is present in the acetal reaction. According to the method of claim 1, wherein the mixture containing the compound of the formula (I) is purified by a separation technique.